Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR). This study reports differences in the metabolic and...

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Autores: Brasil, Sandra, Richard, Eva, Jorge-Finnigan, A., Leal, Fátima, Merinero, Begoña, Banerjee, R., Desviat, Lourdes R., Ugarte, Magdalena, Pérez, Belén
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/139926
Acceso en línea:http://hdl.handle.net/10261/139926
Access Level:acceso abierto
Palabra clave:MMAB gene
Mutation
methylmalonic aciduria
mitochondrial function
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spelling Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studiesBrasil, SandraRichard, EvaJorge-Finnigan, A.Leal, FátimaMerinero, BegoñaBanerjee, R.Desviat, Lourdes R.Ugarte, MagdalenaPérez, BelénMMAB geneMutationmethylmalonic aciduriamitochondrial function© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR). This study reports differences in the metabolic and disease outcomes of two pairs of siblings with MMA cblB type, respectively harbouring the novel changes p.His183Leu/p.Arg190dup (P1 and P2) and the previously described mutations p.Ile96Thr/p.Ser174fs (P3 and P4). Expression analysis showed p.His183Leu and p.Arg190dup to be destabilizing mutations. Both were associated with reduced ATR stability and a shorter half-life than wild-type ATR. Analysis of several parameters related to oxidative stress and mitochondrial function showed an increase in reactive oxygen species (ROS) content, a decrease in mitochondrial respiration and changes in mitochondria morphology and structure in patient-derived fibroblasts compared to control cells. The impairment in energy production and the presence of oxidative stress and fission of the mitochondrial reticulum suggested mitochondrial dysfunction in cblB patients' fibroblasts. The recovery of mitochondrial function should be a goal in efforts to improve the clinical outcome of MMA cblB type.Ministerio de Economía y Competividad (SAF2010-15284 to E. R.) and the National Institutes of Health (DK45776 to R. B.). S. B. was supported by a grant from the Fundação para a Ciência e Tecnologia of Portugal (SFRH/BD/45753/2008). An institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa is gratefully acknowledged.Peer ReviewedBlackwell PublishingMinisterio de Economía y Competitividad (España)Ministerio de Sanidad, Servicios Sociales e Igualdad (España)Fundação para a Ciência e a Tecnologia (Portugal)Fundación Ramón ArecesConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2016201620152016info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/139926reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1399262026-05-22T06:33:51Z
dc.title.none.fl_str_mv Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies
title Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies
spellingShingle Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies
Brasil, Sandra
MMAB gene
Mutation
methylmalonic aciduria
mitochondrial function
title_short Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies
title_full Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies
title_fullStr Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies
title_full_unstemmed Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies
title_sort Methylmalonic aciduria cblB type: Characterization of two novel mutations and mitochondrial dysfunction studies
dc.creator.none.fl_str_mv Brasil, Sandra
Richard, Eva
Jorge-Finnigan, A.
Leal, Fátima
Merinero, Begoña
Banerjee, R.
Desviat, Lourdes R.
Ugarte, Magdalena
Pérez, Belén
author Brasil, Sandra
author_facet Brasil, Sandra
Richard, Eva
Jorge-Finnigan, A.
Leal, Fátima
Merinero, Begoña
Banerjee, R.
Desviat, Lourdes R.
Ugarte, Magdalena
Pérez, Belén
author_role author
author2 Richard, Eva
Jorge-Finnigan, A.
Leal, Fátima
Merinero, Begoña
Banerjee, R.
Desviat, Lourdes R.
Ugarte, Magdalena
Pérez, Belén
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Sanidad, Servicios Sociales e Igualdad (España)
Fundação para a Ciência e a Tecnologia (Portugal)
Fundación Ramón Areces
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv MMAB gene
Mutation
methylmalonic aciduria
mitochondrial function
topic MMAB gene
Mutation
methylmalonic aciduria
mitochondrial function
description © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR). This study reports differences in the metabolic and disease outcomes of two pairs of siblings with MMA cblB type, respectively harbouring the novel changes p.His183Leu/p.Arg190dup (P1 and P2) and the previously described mutations p.Ile96Thr/p.Ser174fs (P3 and P4). Expression analysis showed p.His183Leu and p.Arg190dup to be destabilizing mutations. Both were associated with reduced ATR stability and a shorter half-life than wild-type ATR. Analysis of several parameters related to oxidative stress and mitochondrial function showed an increase in reactive oxygen species (ROS) content, a decrease in mitochondrial respiration and changes in mitochondria morphology and structure in patient-derived fibroblasts compared to control cells. The impairment in energy production and the presence of oxidative stress and fission of the mitochondrial reticulum suggested mitochondrial dysfunction in cblB patients' fibroblasts. The recovery of mitochondrial function should be a goal in efforts to improve the clinical outcome of MMA cblB type.
publishDate 2015
dc.date.none.fl_str_mv 2015
2016
2016
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/139926
url http://hdl.handle.net/10261/139926
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Blackwell Publishing
publisher.none.fl_str_mv Blackwell Publishing
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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